Pancreatic cancer is one of the deadliest types of cancer; In the US, it is estimated that more than 88 percent of people will die from the disease within five years of being diagnosed. One reason for this dismal prognosis is that most pancreatic cancers are diagnosed after the disease has already spread or metastasized to other parts of the body. Another reason is that pancreatic cancers are particularly difficult to treat, as these tumors are often resistant to standard anti-cancer drugs.
NIBIB-funded researchers are developing a new method to treat this deadly disease. His studyrecently published in Nature Biomedical Engineeringcombined an injectable radioactive gel with systemic chemotherapy in multiple mouse models of pancreatic cancer. The treatment resulted in tumor regression in all models evaluated, an unprecedented result for this genetically diverse and aggressive cancer type.
“Radiation treatments are typically administered externally, which exposes healthy tissue to radiation and limits the dose a tumor receives, ultimately limiting their effectiveness,” said David Rampulla, Ph.D., division director of Discovery Science & Technology at NIBIB. “The radioactive biomaterial investigated in this preclinical study can be injected directly into the tumor, allowing for a localized approach. Additionally, this biodegradable biomaterial allows for higher cumulative radiation doses than other implantable radiation treatments.”
Brachytherapy, in which a radiation source is placed inside the body, can be used to treat several different types of cancer. Early-stage prostate cancer, for example, can be treated with “seed” brachytherapy, in which many small metal seeds containing a radioactive substance are implanted in the prostate. While these seeds can limit the exposure of healthy tissues to radiation, their metal coating prevents the use of powerful radiation particles, known as alpha and beta emitters, which are more effective in killing cancer cells. Additionally, due to their small size, around 100 seeds are typically needed for prostate cancer treatment (and each individual seed requires one injection). To date, brachytherapy approaches have not improved clinical outcomes among patients with pancreatic cancer.
The current study is investigating a new type of brachytherapy. Instead of delivering radiation through a metal seed or catheter, the study authors are investigating the use of a radioactive biopolymer that is injected directly into the tumor. In addition to being biodegradable, the biopolymer has a unique property: it has been designed to go from a liquid state at room temperature to a gel-like state when heated to body temperature. As the biopolymer solidifies, it remains within the tumor and cannot easily spread to surrounding healthy tissues.
“Our biopolymer is derived from elastin, an abundant protein found in connective tissues throughout our body,” explained first author Jeff Schaal, Ph.D., who performed this work at Duke University. “By modifying the composition of this biopolymer, we can control the exact temperature at which it goes from liquid to gel. And because we are not enclosing the radioactive polymer inside a protective metal seed, we can use different, more potent isotopes, allowing us to deliver a higher radiation dose than conventional seed brachytherapy.”
The radioactive isotope used in this proof-of-concept treatment is iodine-131 (or I-131), which releases high-energy particles known as beta particles. Beta particles damage DNA and kill irradiated cells, but they can’t travel very far: only a few millimeters (so off-target toxicity is limited). I-131 has been used to treat thyroid cancer for decades and has a well-established safety profile, Schaal said.
Sometimes pancreatic cancer is treated with a combination of radiation and specific chemotherapy agents that make the radiation more effective. These “radiosensitizing” drugs work by prolonging the cell’s replication process, specifically when its DNA is exposed, Schaal explained. Exposed DNA is more sensitive to radiation and more likely to suffer irreparable damage, ultimately leading to cell death.
In combination with a radiosensitizing chemotherapeutic known as paclitaxel, the study authors evaluated their radioactive biopolymer in several different models of pancreatic cancer, carefully selected to reflect different aspects of pancreatic cancer (e.g., common mutations, tumor characteristics, tumor density, or resistance to treatment). Among all models tested, almost all mice responded, meaning the tumors shrank or disappeared completely. “The response rates we saw in our models were unprecedented,” Schaal said. “After a thorough review of the literature, we have yet to find another treatment regimen that demonstrates such a robust response in multiple, genetically diverse models of pancreatic cancer.” Additionally, in some mice, the tumors never returned during the course of the study.
When the study authors evaluated a current clinical treatment regimen (paclitaxel plus external beam radiation), the response rates were not as impressive: the rate of tumor growth was only inhibited, rather than the tumors shrinking or disappearing. “Unlike external beam radiation, which is delivered in short bursts, our brachytherapy approach delivers radiation continuously,” Schaal explained. “We found that this continuous beta particle radiation altered the tumor microenvironment and allowed paclitaxel to better penetrate the tumor core, allowing for a synergistic therapeutic effect.”
Importantly, the researchers did not observe any acute toxicity problems during the course of their study, with negligible amounts of radioactivity accumulating in critical organs of the mice. They have previously reported that its radioactive biopolymer biodegrades safely, and that the gel’s half-life (approximately 95 days) far exceeds the half-life of I-131 (approximately eight days).
The authors did not evaluate their treatment in metastatic disease, but the nature of their approach would allow biopolymer injections in multiple locations, such as tumor masses in other organs. And although this study remains in the preclinical stage, the study authors are working to advance this treatment. “Our group has partnered with clinical researchers to develop and optimize our system for endoscope-guided delivery in a larger animal model,” said senior author Ashutosh Chilkoti, Ph.D., professor in the Department of Biomedical Engineering at Duke University. “However, the challenge in bringing this treatment (or any new treatment) to patients is finding the support to take it into clinical trials.”
This study was funded by a NIBIB grant (R01EB000188) and a grant from the National Cancer Institute (NCI; grant R35CA197616).
This Science Highlight describes a basic research finding. Basic research increases our understanding of human behavior and biology, which is critical to promoting new and better ways to prevent, diagnose, and treat diseases. Science is an unpredictable and incremental process: each research advance builds on past discoveries, often in unexpected ways. Most clinical advances would not be possible without knowledge of fundamental basic research.
